Cannabinergic Receptor Antagonists for Nicotine Addiction

大麻素受体拮抗剂治疗尼古丁成瘾

• 批准号: 8713752
• 负责人: Shakiru Olajire Alapafuja
• 金额: $ 22.18万
• 依托单位: MAKSCIENTIFIC, LLC
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713752
• 关键词: Address; Adverse effects; Affinity; Agonist; Anhedonia; Animals; Attenuated; Back; Behavioral; Binding; Biological Assay; Biological Availability; Brain; CNR1 gene; Cannabinoids; Chemistry; Clinical; Computer Simulation; Development; Discrimination; Distress; Dose; Evaluation; Exhibits; Goals; Health Hazards; Hepatic; Hospitals; Human; In Vitro; Intention; Laboratories; Lead; Legal patent; Letters; Ligands; Liver Microsomes; Measures; Metabolic; Microsomes; Modeling; Motor Activity; Mus; Nicotine; Nicotine Dependence; Nicotinic Agonists; Oral; Penetration; Pharmaceutical Preparations; Pharmacotherapy; Phase; Property; Public Health; Publishing; Pyrazoles; Pyrrolidinones; Rattus; Relative (related person); Research; Resistance; Rewards; Rodent; Selection Criteria; Self Administration; Series; Smoking; Stimulus; Structure; Taste Perception; Testing; Therapeutic; Time; Universities; Work; addiction; analog; attenuation; base; combat; commercialization; design; drug discovery; in vivo; liquid chromatography mass spectrometry; man; nonhuman primate; novel; novel strategies; pharmacophore; phase 2 study; pre-clinical; preclinical study; programs; public health relevance; receptor; rimonabant; screening; smoking cessation; success; varenicline

DESCRIPTION (provided by applicant): Existing evidence in animals and man indicates that blockade of the CB1 receptor may offer an effective approach for combating nicotine addiction. Early studies in humans have documented these effects. This Phase I application proposes studies to design advanced CB1 pyrrolidinone antagonists toward the development of medications for smoking cessation. Our intention is to: 1) develop CB1 antagonists with limited inverse agonist or neutral antagonist activity and 2) to characterize their ability to attenuate th effects of nicotine in behavioral screening assays in rats that can be conducted within the limits of a Phase I program. We expect to forward the most successful compounds from Phase I into Phase II studies, in which we shall pursue a more detailed lead optimization program, characterize compounds for side-effect liability, and evaluate their ability to reduce addiction-related effects of nicotine in established, addiction-related, self- administration studies in nonhuman primates. Such Phase II studies should lead to one pre-clinical candidate and 2-3 back-ups.

描述（由申请方提供）：动物和人体中的现有证据表明，阻断CB 1受体可能是对抗尼古丁成瘾的有效方法。早期的人类研究已经证明了这些影响。这项I期申请提出了设计先进的CB 1吡咯烷酮拮抗剂的研究，以开发戒烟药物。我们的目的是：1）开发具有有限反向激动剂或中性拮抗剂活性的CB 1拮抗剂，2）表征其在大鼠行为筛选试验中减弱尼古丁效应的能力，该试验可在I期项目的限度内进行。我们希望将最成功的化合物从I期转入II期研究，在II期研究中，我们将实施更详细的先导化合物优化计划，表征化合物的副作用倾向，并在非人灵长类动物中已建立的成瘾相关自我给药研究中评价其降低尼古丁成瘾相关作用的能力。此类II期研究应产生一个临床前候选药物和2-3个备用药物。